Alzheimer's Disease (AD) is a degenerative disorder of the human central nervous system characterized by progressive memory impairment and cognitive and intellectual decline during mid to late adult life (Katzman, 1986, N. Eng. J. Med. 314:964–973). The disease is accompanied by a constellation of neuropathologic features principal amongst which are the presence of extracellular amyloid or senile plaques, and neurofibrillary tangles in neurons. The etiology of this disease is complex, although in some families it appears to be inherited as an autosomal dominant trait. Genetic studies have identified three genes associated with the development of AD, namely: (1) β-amyloid precursor protein (βAPP) (Chartier-Harlin et al., 1991, Nature 353:844–846; Goate et al., 1991, Nature 349:704–706; Murrell et al., 1991, Science 254:97–99; Karlinsky et al., 1992, Neurology 42:1445–1453; Mullan et al., 1992, Nature Genetics 1:345–347); (2) presenilin-1 (PS1) (Sherrington et al., 1995, Nature 375:754–760); and (3) presenilin-2 (PS2) (Rogaev et al., 1995, Nature 376:775–778; Levy-Lehad et al., 1995, Science 269:970–973).
The presenilin genes (presenilin 1—PS1 and presenilin 2—PS2) encode homologous polytopic transmembrane proteins that are expressed at low levels in intracellular membranes including the nuclear envelope, the endoplasmic reticulum, the Golgi apparatus and some as yet uncharacterised intracytoplasmic vesicles in many different cell types including neuronal and non-neuronal cells (Sherrington et al., 1995; Rogaev et al., 1995; Levy-Lahad et al., 1995; Doan et al., 1996, Neuron 17:1023–1030; Walter et al., 1996, Molec. Medicine 2:673–691; De Strooper et al., 1997, J. Biol. Chem 272:3590–3598; Lehmann et al., 1997, J. Biol. Chem. 272:12047–12051; Li et al., 1997, Cell 90:917–927). Structural studies predict that the presenilins contain between six and eight transmembrane (TM) domains organized such that the N-terminus, the C-terminus, and a large hydrophilic loop following the sixth TM domain are located in the cytoplasm or nucleoplasm, while the hydrophilic loop between TM1 and TM2 is located within the lumen of membranous intracellular organelles (Doan et al., 1996; De Strooper et al., 1997; Lehmann et al., 1997).
Missense mutations in the PS1 and PS2 genes are associated with the inherited forms of early-onset AD (Sherrington et al., 1995, Nature 375:754–760; Rogaev, et al., 1995, Nature 376:775–778; Levy-Lahad et al, 1995, Science 269: 970–973). Several lines of evidence have also suggested roles in developmental, apoptotic signalling and in the regulation of proteolytic cleavage of the b-amyloid precursor protein (bAPP) (Levitan et al., 1995, Nature 377:351–354; Wong et al., 1997, Nature 387:288–292; Shen et al, 1997, Cell 89:629–639; Wolozin et. al., 1996, Science 274:1710–1713; De Strooper et al., 1998; Nature 391:387–390). Nevertheless, it remains unclear just how these putative functions are mediated, or how they relate to the abnormal metabolism of the βAPP associated with PS1 and PS2 mutations (Martin et al., 1995, NeuroReport 7:217–220; Scheuner et al., 1996, Nature Med. 2:864–870; Citron et al., 1997, Nature Med. 3:67–72; Duff et al., 1996, Nature 383:710–713; Borchelt et al., 1996, Neuron 17:1005–1013).
The identification and cloning of normal as well as mutant PS1 and PS2 genes and gene products are described in detail in copending commonly assigned U.S. application Ser. No. 08/431,048, filed Apr. 28, 1995; Ser. No. 08/496,841, filed Jun. 28, 1995; Ser. No. 08/509,359, filed Jul. 31, 1995; and Ser. No. 08/592,541, filed Jan. 26, 1996, the disclosures of which are incorporated herein by reference.
There is speculation that onset of AD may be associated with aberrant interactions between mutant presenilin proteins and normal forms of PS-interacting proteins, and these changes may increase or decrease interactions present with normal PS1, or cause interaction with a mutation-specific PS-interacting protein. Such aberrant interactions also may result from normal presenilins binding to mutant forms of the PS-interacting proteins. Therefore, mutations in the PS-interacting proteins may also be causative of AD.
While the identification of normal and mutant forms of PS proteins has greatly facilitated development of diagnostics and therapeutics, a need exists for new methods and reagents to more accurately and effectively diagnose and treat AD.